Naphtho[2,3-b][1,4]-thiazine-5,10-diones and 3-substituted-1,4- dioxo-1,4-dihydronaphthalen-2-yl-thioalkanoate derivatives: Synthesis and biological evaluation as potential antibacterial and antifungal agents Vishnu K. Tandon, a, * Hardesh K. Maurya, a Dharmendra B. Yadav, a Ashutosh Tripathi, a Manish Kumar b and Praveen K. Shukla b a Department of Chemistry, Lucknow University, Lucknow 226007, India b Division of Fermentation Technology, Central Drug Research Institute, Lucknow 226001, India Received 12 March 2006; revised 27 July 2006; accepted 11 August 2006 Available online 1 September 2006 Abstract—A series of 3-substituted-1,4-dioxo-1,4-dihydronaphthalen-2-yl-thio-alkanoate derivatives 3–21 and naphtho[2,3-b][1,4]- thiazine-5,10-diones 24 were synthesized and evaluated for their antibacterial and antifungal activities. The structure–activity rela- tionships of these compounds were studied and the results show that the compound 24a exhibited better antibacterial activity than Gentamycin in vitro against Staphylococcus aureus. In addition 24a also imparted marked antifungal activity in vitro against Cryp- tococcus neoformans, Sporothrix schenckii, and Trichophyton mentagraphytes when compared with Fluconazole. Compounds 15, 18, 19, and 21 also exhibited significant antibacterial activity in vitro against S. aureus. Ó 2006 Elsevier Ltd. All rights reserved. The quinone group forms the basis of biological activity of a number of clinical and experimental drugs that are associated with antitumor, antimalarial, antifungal, and antibacterial studies. 1–11 The clinical significance of this class of compounds has stimulated the synthesis and biological evaluation of new agents retaining the ‘core’ quinone moiety. 12–19 The diverse biological effects caused by incorporation of nitrogen or sulfur atoms in five- or six-membered heterocyclic ring retaining the ‘core’ chromophore have been one of the mainstay of structural and chem- ical modifications of this class of compounds. 1–21 This has already led to development of lead molecules I–III (Fig. 1) having pronounced biological effects. 1,3,10,19 In the course of a medicinal chemistry program aimed at the synthesis of new quinone derivatives having both N and S atoms in a six-membered ring as part of heterocy- clic quinone, we have synthesized a series of 3-substitut- ed-1,4-dioxo-1,4-dihydronaphthalen-2-yl-thioalkanoate derivatives 2–21 and naphtho[2,3-b][1,4]-thiazine-5,10- diones 24. The evaluation of antibacterial activities of compounds 2–24 against various strains of the bacteria, for example, Staphylococcus aureus, Streptococcus faecalis, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli was carried out according to the broth microdilution technique described by NCCLS. 22,23 The minimum inhibitory concentration (MIC) and IC 50 of each com- pound were determined against test isolates using this technique. The MICs and IC 50 s of standard antibacteri- al drugs Gentamycin and Ampicillin were determined in 96-well tissue culture plates using Mueller–Hinton broth. Table 1 shows antibacterial activity of compounds 2–24. The antibacterial activity was compared with those of Gentamycin and Ampicillin which were used as positive control in all tests with MIC and IC 50 values expressed in lg/mL. Compound 24a showed better activity than Gentamycin against S. aureus. It also showed 0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2006.08.060 Keywords: Antibacterial; Antifungal; Heterocyclic quinones; Naph- thothiazine-5,10-diones. * Corresponding author. Fax: +91 522 2684388; e-mail: vishnutandon @yahoo.co.in Bioorganic & Medicinal Chemistry Letters 16 (2006) 5883–5887